Eukaryotic chromosomal DNA wraps around core histone proteins, histones H2A, H2B, H3 and H4, etc. to form a basic structure called nucleosome. Further, the nucleosome structures assemble to form a chromatin structure. Post-translational modifications of histones are closely related to the constitution of the chromatin structure, and as the post-translational modification, acetylation, methylation, phosphorylation, ubiquitination and the like are known.
For example, it is thought that histone acetylation is related to gene transcriptional induction, replication, repair and the like.
The histone acetylation is reversibly regulated by a histone acetyltransferase (hereinafter referred to as “HAT”) and a histone deacetylase (hereinafter referred to as “HDAC”).
It is thought that if HDAC is inhibited, histone acetylation by HAT is enhanced and subsequent gene transcriptional induction, replication, repair and the like are activated, and therefore, various diseases considered to be associated with cell proliferation, senescence and the like. Such as cancer, autoimmune diseases, neurodegenerative diseases and infectious diseases can be prevented and/or treated (Protein, Nucleic Acid and Enzyme, Vol. 51. No. 14 (2006), JP-A-2005-272419 and JP-T-2006-517532).
As typical examples of an HDAC inhibitor, butyric acid which has an effect of cell cycle arrest, an effect of normalization and differentiation of transformed cells and the like (J. Biol. Chem., 254, 1716-1723 (1979)), trichostatin A which is a microbial metabolite and has an effect of cell cycle arrest, an effect of induction of differentiation and the like (Cancer Res., 47, 3688-3691 (1987), Exp. Cell Res., 177, 122-131 (1988) and J. Biol. Chem., 265, 17174-17179 (1990)), trapoxin which is a microbial metabolite and has an inhibitory effect of cell proliferation (J. Antibiotics, 43, 1524-1534 (1990) and J. Biol. Chem., 268, 22429-22435 (1993)) and the like are known.
Moreover, the aqueous humor circulation in the eye is closely related to intraocular pressure, and the hindrance of the aqueous humor circulation effect on the intraocular pressure. In particular, when the aqueous humor circulation is hindered, the intraocular pressure is increased to cause a disease considered to be associated with aqueous humor circulation or intraocular pressure such as glaucoma or ocular hypertension.
In general, aqueous humor is produced by filtration or active transport of plasma components and most aqueous humor flows out of the eyeball through the trabecular outflow pathway. That is, it becomes possible to prevent and/or treat a disease considered to be associated with aqueous humor circulation or intraocular pressure by changing the morphology of trabecular meshwork cells with a medicinal agent or the like to reduce the resistance to aqueous humor outflow thereby enhancing aqueous humor outflow.
For example, as a medicinal agent for changing the morphology of trabecular meshwork cells to enhance aqueous humor outflow, latrunculin A (an actin polymerization inhibitor), H-7 (a myosin light chain kinase (MLCK) inhibitor), Y-39983 (a Rho kinase inhibitor) (WO 1997/030701 and WO 2000/009162) and the like are known.
On the other hand, a compound having a thiophenediamine structure is disclosed as an inhibitor of tumor cell proliferation in WO 2005/030704 and 2005/030705. However, there is no specific description regarding a novel thiophenediamine derivative having a urea structure.